The global obesity epidemic is caused by multifactorial interactions between inherited allelic variation and the environment. Other components of obesity, based on variations in epigenetic programming, have been established by human epidemiological and animal studies that link nutritional status in utero and during early post-natal growth to the development of obesity and diabetes in adults. However, the mechanisms associated with these epigenetic contributions to obesity are not well understood. To identify epigenetic determinants of obesity, global analyses of gene expression was used to identify gene targets that are associated with phenotypic variations in the development of diet-induced obesity in a genetically identical population of mice. These analyses identified a set of genes that included imprinted developmental genes, antagonists of Wnt signaling and genes of angiogenesis and vascularization. One of these genes, mesoderm specific transcript (Mest);a maternally imprinted gene localized in the endoplasmic reticulum/Golgi apparatus where it may function as an epoxide hydrolase, lipase or acyltransferase based on homology with members of the 1/2 hydrolase superfamily, is highly expressed when fat mass is rapidly expanding. Mest was shown to be elevated in adipose tissue biopsies of juvenile mice destined to develop diet-induced obesity as adults suggesting that molecular changes regulating it have been established prior to feeding a high fat diet. The positive association of Mest with variations of fat mass expansion in genetically identical mice suggests that epigenetic mechanisms are involved in its regulation. The studies in this proposal will determine the functional role for Mest in fat mass expansion by using mouse models and primary cell lines with targeted deletions for Mest (Aim 1), will identify the molecular/catalytic function of MEST in facilitating fat mass expansion (Aim 2) and will uncover epigenetic mechanisms that regulate Mest by identifying changes in chromatin structure that is associated with variable expression of Mest in adipose tissue of inbred mice fed an obesogenic diet (Aim 3).Understanding the mechanisms that regulate Mest and the catalytic function by which it controls fat mass expansion could identify novel therapeutic targets for the treatment of obesity. PUBLIC HEALTH RELEVANCE: Scientists have shown that factors such as genetics and the environment interact to determine a person's susceptibility to developing diseases such as obesity and diabetes;however, very little is known about the molecular pathways that are involved in these interactions. Therefore, we are studying a mouse model in where all of the individuals are genetically identical to understand the basis for these alterations. We have identified several genes that are associated with variations in obesity and propose to study how one these genes, mesoderm specific transcript, functions in order to determine whether it could be used as drug target for the treatment of obesity.